EP1585483B1 - Formes posologiques de compose topique stabilise de prostaglandine e - Google Patents
Formes posologiques de compose topique stabilise de prostaglandine e Download PDFInfo
- Publication number
- EP1585483B1 EP1585483B1 EP03800371A EP03800371A EP1585483B1 EP 1585483 B1 EP1585483 B1 EP 1585483B1 EP 03800371 A EP03800371 A EP 03800371A EP 03800371 A EP03800371 A EP 03800371A EP 1585483 B1 EP1585483 B1 EP 1585483B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- prostaglandin
- pge
- dosage form
- compound
- percent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- -1 prostaglandin e compound Chemical class 0.000 title claims abstract description 70
- 239000002552 dosage form Substances 0.000 title claims description 23
- 230000000699 topical effect Effects 0.000 title claims description 20
- 239000000203 mixture Substances 0.000 claims abstract description 54
- 239000003961 penetration enhancing agent Substances 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical group CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims abstract description 15
- 239000004067 bulking agent Substances 0.000 claims abstract description 8
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 13
- HSMMSDWNEJLVRY-INIZCTEOSA-N dodecyl (2s)-2-(dimethylamino)propanoate Chemical group CCCCCCCCCCCCOC(=O)[C@H](C)N(C)C HSMMSDWNEJLVRY-INIZCTEOSA-N 0.000 claims description 12
- IPWWTXFQEUNUNX-UHFFFAOYSA-N dodecyl 2-(dimethylamino)propanoate;hydrochloride Chemical group Cl.CCCCCCCCCCCCOC(=O)C(C)N(C)C IPWWTXFQEUNUNX-UHFFFAOYSA-N 0.000 claims description 5
- CBOMORHDRONZRN-QLOYDKTKSA-N prostaglandin E3 Chemical compound CC\C=C/C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O CBOMORHDRONZRN-QLOYDKTKSA-N 0.000 claims description 4
- 239000003125 aqueous solvent Substances 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 abstract description 9
- 239000007787 solid Substances 0.000 abstract description 7
- 239000007788 liquid Substances 0.000 abstract description 4
- 239000007909 solid dosage form Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 235000019441 ethanol Nutrition 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229920001282 polysaccharide Polymers 0.000 description 12
- 150000004676 glycans Chemical class 0.000 description 11
- 239000005017 polysaccharide Substances 0.000 description 11
- 239000003995 emulsifying agent Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 229920002125 SokalanĀ® Polymers 0.000 description 9
- 239000002518 antifoaming agent Substances 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 8
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000008367 deionised water Substances 0.000 description 7
- 229910021641 deionized water Inorganic materials 0.000 description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 230000035515 penetration Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- OMDQUFIYNPYJFM-XKDAHURESA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[[(2r,3s,4r,5s,6r)-4,5,6-trihydroxy-3-[(2s,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methoxy]oxane-3,4,5-triol Chemical class O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@H](O)[C@H](O)O1 OMDQUFIYNPYJFM-XKDAHURESA-N 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 5
- 229920000858 Cyclodextrin Polymers 0.000 description 5
- 229920000926 Galactomannan Polymers 0.000 description 5
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 229940008099 dimethicone Drugs 0.000 description 5
- 239000004205 dimethyl polysiloxane Substances 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 150000003180 prostaglandins Chemical class 0.000 description 5
- RXBQNMWIQKOSCS-UHFFFAOYSA-N (7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl)methanol Chemical compound C1C2C(C)(C)C1CC=C2CO RXBQNMWIQKOSCS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 229960001631 carbomer Drugs 0.000 description 3
- 238000005266 casting Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 229940097362 cyclodextrins Drugs 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229960004592 isopropanol Drugs 0.000 description 3
- 150000002634 lipophilic molecules Chemical class 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920001296 polysiloxane Polymers 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 2
- XMGQYMWWDOXHJM-JTQLQIEISA-N (+)-Ī±-limonene Chemical compound CC(=C)[C@@H]1CCC(C)=CC1 XMGQYMWWDOXHJM-JTQLQIEISA-N 0.000 description 2
- GRWFGVWFFZKLTI-IUCAKERBSA-N (-)-Ī±-pinene Chemical compound CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- NCXUNZWLEYGQAH-UHFFFAOYSA-N 1-(dimethylamino)propan-2-ol Chemical compound CC(O)CN(C)C NCXUNZWLEYGQAH-UHFFFAOYSA-N 0.000 description 2
- KTPHASGENPMMQK-UHFFFAOYSA-N 1-(dimethylamino)propan-2-yl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC(C)CN(C)C KTPHASGENPMMQK-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920000161 Locust bean gum Polymers 0.000 description 2
- RXBQNMWIQKOSCS-RKDXNWHRSA-N Myrtenol Natural products C1[C@H]2C(C)(C)[C@@H]1CC=C2CO RXBQNMWIQKOSCS-RKDXNWHRSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000004353 Polyethylene glycol 8000 Substances 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 201000001880 Sexual dysfunction Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- LRCFXGAMWKDGLA-UHFFFAOYSA-N dioxosilane;hydrate Chemical compound O.O=[Si]=O LRCFXGAMWKDGLA-UHFFFAOYSA-N 0.000 description 2
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 2
- BZEWSEKUUPWQDQ-UHFFFAOYSA-N dyclonine Chemical compound C1=CC(OCCCC)=CC=C1C(=O)CCN1CCCCC1 BZEWSEKUUPWQDQ-UHFFFAOYSA-N 0.000 description 2
- 229960000385 dyclonine Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 235000010420 locust bean gum Nutrition 0.000 description 2
- 239000000711 locust bean gum Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 229940085678 polyethylene glycol 8000 Drugs 0.000 description 2
- 235000019446 polyethylene glycol 8000 Nutrition 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 231100000872 sexual dysfunction Toxicity 0.000 description 2
- 229960004029 silicic acid Drugs 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- DUXYWXYOBMKGIN-UHFFFAOYSA-N trimyristin Chemical compound CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCC DUXYWXYOBMKGIN-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- CCEFMUBVSUDRLG-KXUCPTDWSA-N (4R)-limonene 1,2-epoxide Natural products C1[C@H](C(=C)C)CC[C@@]2(C)O[C@H]21 CCEFMUBVSUDRLG-KXUCPTDWSA-N 0.000 description 1
- ULDHMXUKGWMISQ-VIFPVBQESA-N (S)-(+)-Carvone Natural products CC(=C)[C@H]1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-VIFPVBQESA-N 0.000 description 1
- WUOACPNHFRMFPN-SECBINFHSA-N (S)-(-)-alpha-terpineol Chemical compound CC1=CC[C@@H](C(C)(C)O)CC1 WUOACPNHFRMFPN-SECBINFHSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- 0 *C(CCCCCCC(O)=O)C(CCC1)C1=O Chemical compound *C(CCCCCCC(O)=O)C(CCC1)C1=O 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 description 1
- WDQFELCEOPFLCZ-UHFFFAOYSA-N 1-(2-hydroxyethyl)pyrrolidin-2-one Chemical compound OCCN1CCCC1=O WDQFELCEOPFLCZ-UHFFFAOYSA-N 0.000 description 1
- KIPQYJOLEGBNHQ-UHFFFAOYSA-N 1-(dimethylamino)propan-2-yl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)CN(C)C KIPQYJOLEGBNHQ-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- NQFUSWIGRKFAHK-UHFFFAOYSA-N 2,3-epoxypinane Chemical compound CC12OC1CC1C(C)(C)C2C1 NQFUSWIGRKFAHK-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N 5-oxoproline Chemical compound OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- AMEMLELAMQEAIA-UHFFFAOYSA-N 6-(tert-butyl)thieno[3,2-d]pyrimidin-4(3H)-one Chemical compound N1C=NC(=O)C2=C1C=C(C(C)(C)C)S2 AMEMLELAMQEAIA-UHFFFAOYSA-N 0.000 description 1
- LCWMKIHBLJLORW-UHFFFAOYSA-N 7,7-dimethyl-4-methylidenebicyclo[4.1.0]heptane Chemical compound C1CC(=C)CC2C(C)(C)C21 LCWMKIHBLJLORW-UHFFFAOYSA-N 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 240000008886 Ceratonia siliqua Species 0.000 description 1
- 235000013912 Ceratonia siliqua Nutrition 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 125000003423 D-mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 208000021663 Female sexual arousal disease Diseases 0.000 description 1
- 235000017367 Guainella Nutrition 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- CCEFMUBVSUDRLG-XNWIYYODSA-N Limonene-1,2-epoxide Chemical compound C1[C@H](C(=C)C)CCC2(C)OC21 CCEFMUBVSUDRLG-XNWIYYODSA-N 0.000 description 1
- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229920003091 Methocelā¢ Polymers 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920002509 Poloxamer 182 Polymers 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 241000934878 Sterculia Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- WPMWEFXCIYCJSA-UHFFFAOYSA-N Tetraethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCO WPMWEFXCIYCJSA-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000005250 alkyl acrylate group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- NQFUSWIGRKFAHK-BDNRQGISSA-N alpha-Pinene epoxide Natural products C([C@@H]1O[C@@]11C)[C@@H]2C(C)(C)[C@H]1C2 NQFUSWIGRKFAHK-BDNRQGISSA-N 0.000 description 1
- OVKDFILSBMEKLT-UHFFFAOYSA-N alpha-Terpineol Natural products CC(=C)C1(O)CCC(C)=CC1 OVKDFILSBMEKLT-UHFFFAOYSA-N 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 description 1
- 229930006723 alpha-pinene oxide Natural products 0.000 description 1
- 229940088601 alpha-terpineol Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000000420 anogeissus latifolia wall. gum Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229940085262 cetyl dimethicone Drugs 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 1
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 description 1
- 229960001747 cinchocaine Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 150000003950 cyclic amides Chemical class 0.000 description 1
- 229940086555 cyclomethicone Drugs 0.000 description 1
- 238000002716 delivery method Methods 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- IHSPMDXQWYKHOA-UHFFFAOYSA-N dodecyl 2-(dimethylamino)acetate Chemical compound CCCCCCCCCCCCOC(=O)CN(C)C IHSPMDXQWYKHOA-UHFFFAOYSA-N 0.000 description 1
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000000451 gelidium spp. gum Substances 0.000 description 1
- 235000019314 gum ghatti Nutrition 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid group Chemical group C(CCCCCC)(=O)O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- KUQWZSZYIQGTHT-UHFFFAOYSA-N hexa-1,5-diene-3,4-diol Chemical compound C=CC(O)C(O)C=C KUQWZSZYIQGTHT-UHFFFAOYSA-N 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- TZMQHOJDDMFGQX-UHFFFAOYSA-N hexane-1,1,1-triol Chemical compound CCCCCC(O)(O)O TZMQHOJDDMFGQX-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid group Chemical group C(CCCCC)(=O)O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940033357 isopropyl laurate Drugs 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 239000000231 karaya gum Substances 0.000 description 1
- 229940039371 karaya gum Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 125000005645 linoleyl group Chemical group 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229930007503 menthone Natural products 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- HTLJJHYQRUBBSY-UHFFFAOYSA-N methyl 1-dodecyl-5-oxopyrrolidine-3-carboxylate Chemical compound CCCCCCCCCCCCN1CC(C(=O)OC)CC1=O HTLJJHYQRUBBSY-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical class COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- KUYQDJOFVBGZID-UHFFFAOYSA-N n,n-diethyl-2-methylbenzamide Chemical compound CCN(CC)C(=O)C1=CC=CC=C1C KUYQDJOFVBGZID-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229940093426 poloxamer 182 Drugs 0.000 description 1
- 229940116406 poloxamer 184 Drugs 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 206010036596 premature ejaculation Diseases 0.000 description 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- GRWFGVWFFZKLTI-UHFFFAOYSA-N rac-alpha-Pinene Natural products CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003445 sucroses Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- UUJLHYCIMQOUKC-UHFFFAOYSA-N trimethyl-[oxo(trimethylsilylperoxy)silyl]peroxysilane Chemical compound C[Si](C)(C)OO[Si](=O)OO[Si](C)(C)C UUJLHYCIMQOUKC-UHFFFAOYSA-N 0.000 description 1
- 229940113164 trimyristin Drugs 0.000 description 1
- RMNIZOOYFMNEJJ-UHFFFAOYSA-K tripotassium;phosphate;hydrate Chemical compound O.[K+].[K+].[K+].[O-]P([O-])([O-])=O RMNIZOOYFMNEJJ-UHFFFAOYSA-K 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- This application relates to room temperature stable, non-aqueous prostaglandin E compound dosage forms suitable for the treatment of sexual dysfunction in male as well as female patients.
- Prostaglandins may exhibit vasodilation or vasoconstriction, smooth muscle stimulation or depression.
- Prostaglandins of the E group such as Prostaglandin E 1 (PGE 1 ) has been reported as having utility for the treatment of sexual erectile dysfunction when injected intracavemously as an aqueous solution in physiological saline, Mahmond et al., J. Urology 147:623-626 (1992 ), or applied topically.
- the prostaglandins, such as PGE 1 are relatively insoluble in water, and are also relatively unstable. As a result, prostaglandin solutions for injection are prepared shortly prior to use, a relatively inconvenient expedient.
- US 5,942,545 describes a composition for topical transdermal administration based on prostaglandin E 1 and comprising 1,3-dioxane, 1,3-dioxolane or acetal as skin permeation enhancer.
- the composition may be provided with the enhancer compound maintained separate from the PGE-1 component.
- US 6,046,244 describes a topical composition comprising PGE-1 and a penetration enhancer which is an alkyl-2-(N,N-disubstituted amino)-alkanoate ester, an (N,N-disubstituted amino)-alkanol alkanoate, or a mixture thereof.
- the present invention relates to a packaged, multi-component dosage form which comprises a sealed actives compartment containing a non-aqueous pharmacologically acceptable composition containing a compound of prostaglandin E group selected from the group consisting of prostaglandin E 1 , prostaglandin E 2 , prostaglandin E 3 , and pharmaceutically acceptable salts thereof, a bulking agent therefor and a skin permeation enhancer, and a sealed inerts compartment containing a physiologically compatible, viscous topical delivery vehicle containing water and having a viscosity of at least 50 cps, wherein the skin permeation enhancer is a member of the group consisting of an alkyl-2-(N-substituted amino)- alkanoate, an (N-substituted amino)-alkanol alkanoate, a pharmaceutically acceptable salt thereof, and a mixture thereof.
- a compound of prostaglandin E group selected from the group consisting of prostaglandin E 1
- the prostaglandin E group compound is dispersed substantially uniformly in a carrier sheet.
- the prostaglandin E group compound is dispersed substantially uniformly in a water-soluble carrier sheet or in a carrier sheet that is soluble in a physiologically compatible non-aqueous solvent.
- the viscous topical delivery vehicle is a cream, a gel or an ointment.
- the skin permeation enhancer may be selected from dodecyl-2-(N,N-dimethylamino)-propionate, and dodecyl-2-(N,N-dimethylamino)-propionate hydrochloride, and may be crystalline dodecyl-2-(N,N-dimethylamino)-propionate hydrochloride.
- said inerts compartment also contains a skin permeation enhancer.
- Non-aqueous compositions that include the compound together with a bulking agent that can be a non-aqueous liquid, or a solid in sheet, film, or powder form.
- a skin penetration enhancer can be present.
- a packaged, paired compartment dosage form comprises a sealed actives compartment and a sealed inerts compartment.
- Compound of prostaglandin E group is contained within the actives compartment together with a bulking agent, and the skin penetration enhancer.
- a physiologically compatible viscous topical delivery vehicle is contained within the inerts compartment and is combined with the contents of the actives compartment prior to use, preferably just prior to use.
- a skin penetration enhancer can be included in the inerts compartment in addition to a skin penetration enhancer in the actives compartment.
- the present, dosage forms containing stabilized compound of the prostaglandin E group are useful for amelioration of sexual dysfunction in human patients, e.g., male impotence, premature ejaculation, female sexual arousal disorder, and the like.
- Prostaglandin E is a known compound that can be represented by the formula
- PGE compounds Compounds derived from the foregoing structure and having the 9-oxo, 11 ā -hydroxy substituents as well as unsaturation in the side chains are known as compounds of the prostaglandin E group, hereinafter collectively referred to as PGE compounds.
- the compounds of this group include prostaglandin E 1 (PGE 1 ) represented by the formula prostaglandin E 2 (or PGE 2 ) represented by the formula prostaglandin E 3 (or PGE 3 ) represented by the formula as well as the pharmaceutically acceptable salts thereof.
- PGE compounds have useful therapeutic activity as vasodilators and have been utilized to treat male and female sexual disorders, to control lipid metabolism, to treat ulcers, to treat inflammatory skin lesions, and the like therapeutic applications.
- PGE compounds are relatively unstable, however, and tend to decompose, especially in aqueous solutions or in an aqueous environment.
- PGE compounds can be incorporated as substantially uniformly distributed solids in a sheet-form material, i.e., sheet or film, of a physiologically compatible polymeric material; e.g., a cellulosic ether such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and the like, a polysaccharide such as starch, polyvinylpyrrolidone, and the like:
- Sheet-form materials having a thickness of no more than about 10 mils are commonly referred to as films, and those having a thickness of more than about 10 mils are commonly referred to as sheets.
- sheet-form refers to sheets as well as films.
- the sheet-form material can be a solid or a porous material, e.g., a sponge or the like.
- the sheet-form material containing a PGE compound dispersed therein can be converted into discs, tablets, pellets, and the like, if desired.
- the PGE compound-bearing sheet form materials can also include physiologically compatible plasticizers, solubility enhancers (e.g., hydroxypropyl-beta-cyclodextrin), and the like.
- PGE-bearing sheet-form materials can be prepared by first forming a solution of the desired PGE compound in a non-aqueous solvent such as a C 2 to C 4 aliphatic alcohol, e.g., methanol, ethanol, propanol, isopropanol, n-butanol and the like, together with the polymeric material, with or without a skin penetration enhancer, then casting the solution continuously on a roll or batchwise in a shallow dish or pan, and thereafter evaporating the solvent therefrom.
- the resulting sheet or film has the PGE compound substantially uniformly distributed throughout in an non-aqueous medium that can be readily subdivided and apportioned into desired unit doses each having a predetermined PGE content.
- the cast sheet or film can also be retained on a solid surface for storage and dissolved immediately prior to use.
- the foregoing unit doses can be utilized to provide packaged, paired compartment dosage forms in which an actives compartment contains the PGE compound unit dose and an inerts compartment contains the delivery vehicle for a topical application.
- the actives compartment can also contain the PGE compound together with a bulking agent in a non-aqueous liquid, particulate or granular form.
- Suitable liquid bulking agents are silicone oils such as the polydimethylsiloxanes, e.g., cyclomethicone USP, dimethicone USP; and the like.
- Suitable solid bulking agents for this particular purpose are the cyclodextrins such as hydroxypropyl-beta-cyclodextrin, beta cyclodextrin, gamma cyclodextrin, and the like, the polysacharides such as starches, gums, and the like polyvinylpyrrolidone, polyvinyl alcohol, the methyl celluloses, sugars, and the like.
- a particularly preferred dosage form comprises at least one PGE compound, preferably PGE 1 , and an alkyl (N-substituted amino) ester, both substantially uniformly distributed in the carrier sheet or admixed with one another in an actives compartment of a packaged paired-compartment dosage form.
- PGE 1 and PGE 2 are particularly preferred vasoactive agents for the present purposes.
- PGE 1 and PGE 2 are well known to those skilled in the art. Reference may be had to various literature references for its pharmacological activities, side effects and normal dosage ranges. See for example, Physician's Desk Reference, 51st Ed. (1997 ), The Merck Index, 12th Ed., Merck & Co., N.J. (1996 ), and Martindale The Extra Pharmacopoeia, 28th Ed., London, The Pharmaceutical Press (1982 ). Prostaglandin E 1 as well as other PGE compounds referenced herein are intended to compass also the pharmaceutically acceptable derivatives thereof, including physiologically compatible salts and ester derivatives.
- the quantity of PGE compound, such as PGE 1 , present in the dosage form is a therapeutically effective amount and necessarily varies according to the desired dose for a particular treatment regimen.
- the present dosage formes can contain about 0.05 to about 25 weight percent of PGE compound, based on the total weight of the composition, preferably about 0.1 to about 15 weight percent of the PGE compound.
- a component of the dosage-form is the skin penetration enhancer.
- the penetration enhancer can be an alkyl-2-(N-substituted amino)-alkanoate, an (N-substituted amino)-alkanol alkanoate, or a mixture of these.
- alkyl-2-(N-substituted amino)-alkanoates and (N-substituted amino)-alkanol alkanoates can be grouped together under the term alkyl (N-substituted amino) esters.
- Alkyl-2-(N-substituted amino)-alkanoates suitable for use in the present invention can be represented as follows: wherein n is an integer having a value in the range of about 4 to about 18; R is a member of, the group consisting of hydrogen, C 1 to C 7 alkyl, benzyl and phenyl; R 1 and R 2 are members of the group consisting of hydrogen and C 1 to C 7 alkyl; and R 3 and R 4 are members of the group consisting of hydrogen, methyl and ethyl.
- alkyl (N,N-disubstitutedamino)-alkanoates such as C 4 to C 18 alkyl(N,N-disubstituted amino)-acetates and C 4 to C 18 alkyl (N,N-disubstituted amino)-propionates and pharmaceutically acceptable salts and derivatives thereof.
- Exemplary specific alkyl-2-(N,N-disubstituted amino)-alkanoates include dodecyl 2-(N,N-dimethylamino)-propionate; and dodecyl 2-(N,N-dimethylamino)-acetate;
- alkyl-2-(N-substituted amino)-alkanoates are known.
- dodecyl 2-(N,N-dimethylamino)-propionate is available from Steroids, Ltd., Chicago, IL.
- alkyl-2-(N,N-substituted amino)-alkanoates can be synthesized from readily available compounds as described in U.S. Patent No. 4,980,378 to Wong et al. , which is incorporated herein by reference to the extent that it is not inconsistent.
- alkyl-2-(N,N-disubstituted amino)-alkanoates are readily prepared via a two-step synthesis.
- long chain alkyl chloroacetates are prepared by reaction of the corresponding long chain alkanols with chloromethyl chloroformate or the like in the presence of an appropriate base such as triethylamine, typically in a suitable solvent such as chloroform.
- the reaction can be depicted as follows: wherein R, R 3 , R 4 and n are defined as above.
- the reaction temperature may be selected from about 10 degrees Celsius to about 200 degrees Celsius or reflux, with room temperature being preferred.
- the use of a solvent is optional. If a solvent is used, a wide variety of organic solvents may be selected.
- Choice of a base is likewise not critical.
- Preferred bases include tertiary amines such as triethylamine, pyridine and the like. Reaction time generally extends from about one hour to three days.
- the long chain alkyl chloroacetate is condensed with an appropriate amine according to the scheme: wherein R, R 1 , R 2 , R 3 , and R 4 are defined as before.
- Excess amine reactant is typically used as the base and the reaction is conveniently conducted in a suitable solvent such as ether.
- This second step is preferably run at room temperature, although temperature may vary. Reaction time usually vanes from about one hour to several days. Conventional purification techniques can be applied to ready the resulting ester for use in a pharmaceutical compound.
- Suitable (N-substituted amino)-alkanol alkanoates can be represented by the formula: wherein n is an integer having a value in the range of about 5 to about 18; y is an integer having a value in the range of 0 to about 5; and R 1 , R 2 , R 3 , R 4 R 5 , R 6 and R 7 , are members of the group consisting of hydrogen, C 1 to C 8 alkyl, and C 1 to C 8 aryl; and R 8 is a member of the group consisting of hydrogen, hydroxyl, C 1 to C 8 alkyl, and C 1 to C 8 aryl.
- (N-substituted amino)-alkanol alkanoates such as C 5 to C 18 carboxylic acid esters and pharmaceutically acceptable salts thereof.
- Exemplary specific (N,N-disubstituted amino)-alkanol alkanoates include 1-(N,N-dimethylamino)-2-propanol dodecanoate; 1-(N,N-dimethylamino)-2-propanol myristate; 1-(N,N-dimethylamino)-2-propanol oleate;
- the (N,N-disubstituted amino)-alkanol alkanoates are readily prepared by reacting the corresponding aminoalkinol with lauroyl chloride in the presence of triethylamine.
- a solvent such as chloroform is optional but preferred.
- 1-(N,N-dimethylamino)-2-propanol can be reacted with lauroyl chloride in chloroform and in the presence of triethylamine to form 1-(N,N-dimethylamino)-2-propanol dodecanoate.
- dodecyl 2-(N,N-dimethylamino)-propionate and crystalline salts thereof are generally preferred.
- the preparation of such crystalline salts is described in U.S. Patent No. 6,118,020 to Buyuktimkin et al .
- the penetration enhancer is present in an amount sufficient to enhance the penetration of the PGE compound into tissue.
- the specific amount varies necessarily according to the desired release rate and specific form of PGE compound used. Generally, this amount is in the range of about 0.01 percent to about 20 percent, based on the total weight of the composition to be administered to a patient.
- the desired release rate, including controlled or sustained release of the active compound can also be modulated by selection of the topical delivery vehicle, e.g., a hydrophobic vehicle such as polydimethylsiloxanes and the like. Carboxy-terminated polydimethylsiloxanes can also enhance skin permeation by the active compound.
- a hydrophobic vehicle such as polydimethylsiloxanes and the like.
- Carboxy-terminated polydimethylsiloxanes can also enhance skin permeation by the active compound.
- Natural and modified polysaccharide gums can also be present as part of the carrier sheet or the topical delivery vehicle.
- Suitable representative gums are the natural and modified galactomannan gums.
- a galactomannan gum is a carbohydrate polymer containing D-galactose and D-mannose units, or other derivatives of such a polymer.
- galactomannans There is a relatively large number of galactomannans, which vary in composition depending on their origin.
- the galactomannan gum is characterized by a linear structure of ā -D-mannopyranosyl units linked (1 ā 4). Single membered ā -D-mannopyranosyl units, linked (1 ā 6) with the main chain, are present as side branches.
- Galactomannan gums include guar gum; which is the pulverized endosperm of the seed of either of two leguminous plants ( Cyamposis tetragonalobus and psoraloids ) and locust bean gum, which is found in the endosperm of the seeds of the carbotree ( ceratonia siliqua ).
- Suitable modified polysaccharide gums include ethers of natural or substituted polysaccharide gums, such as carboxylmethyl ethers, ethylene glycol ethers and propylene glycol ethers.
- composition of the present invention may contain a mixture of various gums, or mixture of gums and acidic polymers.
- Gums, and galactomannan gums in particular are well-known materials. See for instance, Industrial Gums:Polysaccharides & Their Derivatives, Whistler R.L. and BeMiller J.N. (eds.), 3rd Ed. Academic Press (1992 ) and Davidson R.L., Handbook of Water-Soluble Gums and Resin, McGraw-Hill, Inc., N.Y. (1980 ). Most gums are commercially available in various forms, commonly a powder, and ready for use in food and topical compositions. For example, locust bean gum in powdered form is available from Tic Gums Inc. (Belcam, MD).
- the polysaccharide gums are present in the range of about 0.1 percent to about 5 percent, based on the total weight of the composition, with the preferred range being in the range of about 0.5 percent to 3 percent. In one preferred embodiment, about 2.5 percent by weight of a polysaccharide gum is present.
- polyacrylic acid polymer An optional alternative to the polysaccharide gum is a polyacrylic acid polymer.
- a common variety of polyacrylic acid polymer is known generically as "carbomer.ā
- Carbomer is polyacrylic acid polymers lightly cross-linked with polyalkenyl polyether. It is commercially available from the B.F. Goodrich Company (Akron, Ohio) under the designation "CARBOPOLTM.ā
- CARBOPOL 940 A particularly preferred variety of carbomer is that designated as "CARBOPOL 940.ā
- polyacrylic acid polymers suitable for use are those commercially available under the designation "PemulenTMā (B.F. Goodrich Company) and "POLYCARBOPHILTMā (A.H. Robbins, Richmond, VA).
- the PemulenTM polymers are copolymers of C 10 to C 30 alkyl acrylates and one or more monomers of acrylic acid, methacrylic acid or one of their simple esters crosslinked with an allyl ether of sucrose or an allyl ether of pentaerythritol.
- the POLYCARBOPHILTM product is polyacrylic acid cross-linked with divinyl glycol.
- the concentration of lipophilic compound required necessarily varies according to other factors such as the desired semi-solid consistency and the desired skin penetration promoting effects.
- concentration of lipophilic compound is the range of about 0.5 percent to about 40 percent by weight based on the total weight of the composition.
- the preferred topical composition contains lipophilic compound in the range of about 7 percent to about 40 percent by weight based on the total weight of the composition.
- the suitable amount of alcohol is in the range of about 0.5 percent to about 75 percent. In one preferred embodiment, the amount of alcohol is in the range of about 5 percent to about 15 percent, while that of aliphatic ester is in the range of about 2 percent to about 15 percent (again based on the total weight of the composition). In another preferred embodiment, the amount of alcohol is in the range of about 0.5 percent to about 10 percent, while that of aliphatic ester is in the range from zero percent to about 10 percent (again based on the total weight of the composition).
- An optional, but preferred, component is an emulsifier.
- a suitable emulsifier generally will exhibit a hydrophilic-lipophilic balance number greater than 10.
- Sucrose esters, and specifically sucrose stearate can serve as emulsifiers for the composition.
- Sucrose stearate is a well-known emulsifier available from various commercial sources. When an emulsifier is used, sucrose stearate, present in an amount up to about 2 percent, based on the total weight of the composition, is preferred. The preferred amount of sucrose stearate emulsifier can also be expressed as a weight ratio of emulsifier to polysacharide gum.
- Suitable emulsifiers are the polyoxyethylene sorbitan esters, long chain alcohols, preferably cetostearyl alcohol, and fatty acid glycerides.
- Suitable polyoxyethylene sorbitan esters include the monolaurate (Tween 20, Span 20) the monopalmitate (Tween 40), the monostearate (Tween 60), and the monooleate (Tween 80) and mixtures thereof.
- Preferred fatty acid glycerides include glyceryl monooleate, triolean, trimyristin and tristearin.
- Another optional ingredient is an antifoam agent, a chemical that reduces the tendency of the finished preparation to generate foam on shaking or agitation.
- Silicones are the preferred antifoam agents; however, a wide variety of alcohols and lipids exhibit similar properties. With the exception of alcohols, the selected antifoam agent must be effective in relatively small concentrations, and are employed in trace amounts.
- Illustrative antifoam agents are dimethicone, cetyl dimethicone, dimethicone silylate, dimethiconol, a mixture of dimethicone and hydrated silica, isopropyl alcohol, hexyl alcohol, trimethylsiloxysilicate, triphenyl trimethicone and the like.
- Particularly preferred antifoam agent is a mixture of dimethicone with an average chain length of 200 to 300 dimethylsiloxane units and hydrated silica, commercially available under the designation SIMBTHICONE USP from Dow Coming Corporation, Michigan.
- the composition can include a buffer system, if desired.
- Buffer systems are chosen to maintain or buffer the pH of compositions within a desired range.
- the term "buffer systemā or ābufferā as used herein refers to a solute agent or agents which, when in a water solution, stabilize such solution against a major change in pH (or hydrogen ion concentration or activity) when acids or bases are added thereto. Solute agent or agents which are thus responsible for a resistance or change in pH from a starting buffered pH value in the range indicated above are well known. While there are countless suitable buffers, potassium phosphate monohydrate has proven effective for compositions of the present invention and is preferred.
- the final pH value of the pharmaceutical composition may vary within the physiological compatible range. Necessarily, the final pH value is one not irritating to human skin and preferably such that transdermal transport of the PGE compound is facilitated. Without violating this constraint, the pH may be selected to improve PGE compound stability and to adjust consistency when required. In one embodiment, the preferred pH value is about 3.0 to about 7.4, more preferably about 3.0 to about 6.5, most preferably from about 3.5 to about 6.0.
- the remaining component of the composition is water, which is necessarily purified, e.g., deionized water.
- water which is necessarily purified, e.g., deionized water.
- Such delivery vehicle compositions contain water in the range of more than about 50 to about 95 percent, based on the total weight of the composition.
- the specific amount of water present is not critical, however, being adjustable to obtain the desired viscosity (usually about 50 cps to about 10,000 cps) and/or concentration of the other components.
- transdermal skin penetration enhancers can also be used to facilitate delivery of the compound of prostaglandin E group.
- Illustrative are sulfoxides such as dimethylsulfoxide (DMSO) and the like; cyclic amides such as 1-dodecylazacycloheptane-2-one.
- amides such as N,N-dimethyl acetamide (DMA) N,N-diethyl toluamide, N,N-dimethyl formamide, N,N-dimethyl octamide, N,N-dimethyl decamide, and the like; pyrrolidone derivatives such as N-methyl-2-pyrrolidone, 2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N-(2-hydroxyethyl)-2-pyrrolidone or fatty acid esters thereof, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-tallowalkylpyrrolidones, and the like; polyols such as propylene glycol, ethylene glycol, polyethylene glycol, dipropylene glycol, glycerol, hexanetriol; and the like; linear and branched fatty acids such as
- organic acids and esters such as salicyclic acid, methyl salicylate; citric acid, succinic acid, and the like.
- PGE coinpound stabilizers such as organic acids and alcohols, cyclodextrins, coloring agents, rheological agents, and preservatives can be added to the extent that they do not limit penetration of the PGE compound.
- ingredients listed above may be combined in any or,der..and manner that produces a stable composition for ultimately receiving the PGE compound, such as PGE 1 and the like, preferably substantially evenly dispersed throughout.
- One available approach to preparing such compositions involve evenly dispersing the polysaccharide gum (or polyacrylic acid) in a premixed water/buffer solution and then thoroughly homogenizing (i.e., mixing) the resulting mixture.
- the emulsifier is added to the water/buffer solution before dispersing the polysaccharide gum.
- Any suitable method of adjusting pH value to the desired level may be used, for example, by adding concentrated phosphoric acid or sodium hydroxide.
- the PGE compound, with a penetration enhancer, is then combined therewith prior to use with mixing.
- composition is ready for topical, intrameatal, or vaginal administration.
- compositions can be used for prolonged treatment of peripheral vascular disease, male impotency and other disorders treated or treatable by PGE compounds while avoiding low bioavailability and rapid chemical decomposition associated with other delivery methods.
- a preparation ready for administration comprises about 0.01 percent to about 5 percent modified polysaccharide gum; about 0.001 percent to about 1 percent of a PGE compound, preferably PGE 1 , or a pharmaceutically acceptable salt thereof, a lower alkyl ester thereof and mixtures thereof; about 0.5 percent to about 10 percent dodecyl 2-(N,N-dimethylamino)-propionate or a salt thereof; about 0.5 percent to about 10 percent of a lower alcohol selected from the group consisting of ethanol, propanol, isopropanol and mixtures thereof; about 0.5 percent to about 10 percent on an ester selected from the group consisting of ethyl laurate, isopropyl myristate, isopropyl laurate and mixture thereof; based on the weight of the preparation, together with an acid buffer.
- the preparation also comprises up to about 2 percent by weight sucrose stearate.
- compositions which do not adversely affect the effectiveness of the PGE compound will be evident to one skilled in the art, and are within the scope of this invention.
- additional ingredients such as coloring agents, anti-microbial preservatives, emulsifiers, lubricants, perfumes, PGE compound stabilizers, and the like, may be included as long as the resulting preparation retains desirable properties, as described above.
- preservatives are usually added in amounts of about 0.05 to about 0.30%. Suitable preservatives include methylparabens (methyl PABA), propylparabens (propyl PABA) and butylhydroxy toluene (BHT).
- Suitable perfumes and fragrances are known in the art; a suitable fragrance is up to about 5 percent and fragrances are known in the art; a suitable fragrance is up to about 5 percent myrtenol, preferably about 2 percent myrtenol, based on the total weight of the composition.
- the compositions of the present invention can also include a small amount, about 0.01 to about 4 percent by weight, of a topical anesthetic, if desired.
- Typical topical anesthetics include lidocaine, benzocaine, dyclonine, dibucaine, pharmaceutically acceptable salts and mixtures thereof. In one preferred embodiment, the topical anesthetic is about 0.5 percent dyclonine, based on the weight of the composition.
- Illustrative two-compartment dosage forms are set forth below: Amount, parts by weight Actives Compartment Preferred More Preferred PGE 1 0.025-10 0.05-0.5 Dodecyl 2-(N,N-dimethylamino)-propionateā¢HCl 0.025-10 0.05-2.5 Lactose 1-50 2.5-10 Inerts Compartment Hydroxypropyl methyl cellulose 0.05-2.5 1-6 Silicone antifoam agent 0.001-5 0:1-2 Hydroxypropyl- ā -cyclodextririn 0.5-25 1-10 Water (deionized or U.S.P:) 5-75 20-60 Ethanol 5-75 20-60
- preservatives such as methyl paraben, propyl paraben, benzalkonium chloride, benzethonium chloride, and the like, can be included as well.
- Illustrative two-part compositions for casting a PGE 1 -containing film are set forth below.
- Amount, parts by weight Preferred More Preferred Part A PGE 1 0.025-10 0.05-0.5
- Dodecyl 2-(N,N-dimethylamino)-propionateā¢HCl 0.025-10 0.05-2.5 Hydroxypropyl- ā -cyclodextrin 0.05-25 1-10 Part
- B Hydroxypropyl methylcellulose 0.05-25 1-6
- Polyethylene glycol 8000 powder 0.05-25 0.5-5
- Silicone antifoam agent 0.001-5 0.1-2 Hydroxypropyl- ā -cyclodextrin 0.5-25 1-10
- Ethanol 5-75 20-60 Parts A and B are combined with agitation, the resulting mixture is cast as a layer on a surface, and the ethanol is permitted to evaporate to produce a sheet-form material, i.e., either a sheet
- a viscous topical delivery vehicle was prepared by combining hydroxypropyl methyl cellulose (2 grams; Methocel Ā® E4M; Dow Chemical Co.), polyethylene glycol 8000 powder (0.5 grams), deionized water (97.5 grams), and a trace amount of an antifoam agent (Simethicone Ā® ; Dow Coming Corp., Midland, MI).
- Polyethylene glycol powder 0.5 grams; PEG 8000, was added to cold deionized water (50 grams) with stirring until dissolved to produce a cold polyethylene glycol solution.
- the obtained cold and hot solutions were combined with stirring, more deionized water was added to the combined solution (q.s. 100 grams) ; and the produced solution was placed in an ice bath and chilled to below about 30Ā°C. with continuous agitation.
- the pH value of the produced solution was measured as 6.25.
- This solution is suitable as constituent for the inerts compartment of the two-compartment dosage form.
- Ethyl alcohol can be added to produce a solution suitable for casting a sheet-form unit dose such as a film or sheet.
- the contents for the actives compartment was prepared by admixing dry prostaglandin E 1 (0.018 grams) and dodecyl 2-(N,N-dimethylamino)-propionate (0.12grams).
- the actives content prepared as described hereinabove was then combined with three grams of the inerts composition described above to which anhydrous ethyl alcohol (3 grams) was added.
- a clear, viscous gel was obtained, suitable for topical or intrameatal administration.
- the pH value of the obtained gel was measured as 4.5.
- Example 2 A portion of the clear gel produced as described in Example 1 was spread on a glass panel with a 6-mil film spreader and dried for several hours until a film was produced. Upon the addition of a small amount of water (100 milligrams) a one-inch square of film reconstituted into a clear gel within about 15 seconds.
- PGE 1 powder (0.024 grams) was combined with an aqueous solution having the following constituents: Hydroxypropyl methyl cellulose 0.06 grams PEG 8000 powder 0.015 grams Deionized water 2.925 grams Ethyl alcohol, anhydrous 3 grams and prepared in the same manner as described in Example 1, above. The resulting combination of PGE 1 and the aqueous solution was shaken vigorously for 15 to 30 seconds until the PGE 1 went into solution.
- the resulting solution was poured onto a glass panel and dried at ambient temperature for about 3.5 hours.
- a film containing PGE 1 substantially uniformly dispersed therein was obtained.
- Example 3 The procedure of Example 3, above, was used to dissolve PGE 1 (0.024 grams) and dodecyl 2-(N,N-dimethylamino)-propionate (0.03 grams) in an aqueous solution having the following constituents: Hydroxypropyl methyl cellulose 0.06 grams PEG 8000 powder 0.015 grams Deionized water 2.9 grams Ethyl alcohol, anhydrous 3 grams
- the obtained solution was poured onto a glass panel, spread with a 6-mil. film spreader, and dried for about 3.5 hours.
- a dry film containing substantially uniformly dispersed PGE 1 and dodecyl 2-(N,N-dimethylamino)-propionate was obtained.
- the film was readily water miscible.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Pregnancy & Childbirth (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Claims (8)
- Forme galƩnique multicomposant emballƩe, qui comprend un compartiment de constituants actifs contenant une composition non-aqueuse pharmacologiquement acceptable contenant un composƩ du groupe des prostaglandines E choisi dans le groupe consistant en prostaglandine E1, prostaglandine E2, prostaglandine E3, et leurs sels pharmaceutiquement acceptables, un agent pour en augmenter le volume et un renforƧateur de permƩation cutanƩe, et un compartiment de substances inertes fermƩ, contenant un vƩhicule de dƩlivrance topique visqueux, physiologiquement compatible, ayant une viscositƩ d'au moins 50 cps, tandis que le renforƧateur de permƩation cutanƩe est un membre du groupe consistant en un alkyl-2-(amino N-substituƩ)-alcanoate, un alcanoate d'(amino N-substituƩ)-alcanol, un sel pharmaceutiquement acceptable de ceux-ci, et un de leurs mƩlanges.
- Forme galĆ©nique selon la revendication 1, dans laquelle le composĆ© du groupe des prostaglandines E est dispersĆ© de maniĆØre substantiellement uniforme dans une feuille support.
- Forme galĆ©nique selon la revendication 1, dans laquelle le composĆ© du groupe des prostaglandines E est dispersĆ© de maniĆØre substantiellement uniforme dans une feuille support hydrosoluble ou dans une feuille support qui est soluble dans un solvant non-aqueux physiologiquement compatible.
- Forme galĆ©nique selon la revendication 1, dans laquelle le vĆ©hicule de dĆ©livrance topique visqueux est une crĆØme, un gel ou une pommade.
- Forme galƩnique selon la revendication 1, dans laquelle le renforƧateur de permƩation cutanƩe est le dodƩcyl-2-(N,N-dimƩthylamino)-propionate.
- Forme galƩnique selon la revendication 1, dans laquelle le renforƧateur de permƩation cutanƩe est le chlorhydrate de dodƩcyl-2-(N,N-dimƩthylamino)-propionate.
- Forme galƩnique selon la revendication 1, dans laquelle le renforƧateur de permƩation cutanƩe est le chlorhydrate de dodƩcyl-2-(N,N-dimƩthylamino)-propionate cristallisƩ.
- Forme galƩnique selon la revendication 1, dans laquelle ledit compartiment de substances inertes contient Ʃgalement un renforƧateur de permƩation cutanƩe.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/336,481 US6841574B2 (en) | 2003-01-03 | 2003-01-03 | Topical stabilized prostaglandin E compound dosage forms |
US336481 | 2003-01-03 | ||
PCT/US2003/041658 WO2004062632A1 (fr) | 2003-01-03 | 2003-12-31 | Formes posologiques de compose topique stabilise de prostaglandine e |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09013811.6 Division-Into | 2009-11-03 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP1585483A1 EP1585483A1 (fr) | 2005-10-19 |
EP1585483A4 EP1585483A4 (fr) | 2006-04-19 |
EP1585483B1 true EP1585483B1 (fr) | 2010-05-19 |
Family
ID=32681022
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03800371A Expired - Lifetime EP1585483B1 (fr) | 2003-01-03 | 2003-12-31 | Formes posologiques de compose topique stabilise de prostaglandine e |
Country Status (17)
Country | Link |
---|---|
US (1) | US6841574B2 (fr) |
EP (1) | EP1585483B1 (fr) |
JP (2) | JP2006514068A (fr) |
KR (2) | KR20050098853A (fr) |
CN (1) | CN100574763C (fr) |
AT (1) | ATE468098T1 (fr) |
AU (1) | AU2003300113B2 (fr) |
BR (1) | BR0317924A (fr) |
CA (1) | CA2512015C (fr) |
DE (1) | DE60332656D1 (fr) |
DK (1) | DK1585483T3 (fr) |
ES (1) | ES2343246T3 (fr) |
HK (1) | HK1090293A1 (fr) |
IL (1) | IL169425A (fr) |
PT (1) | PT1585483E (fr) |
WO (1) | WO2004062632A1 (fr) |
ZA (1) | ZA200505321B (fr) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050004226A1 (en) * | 1998-12-10 | 2005-01-06 | Nexmed (Holdings), Inc. | Compositions and methods for amelioration of human female sexual dysfunction |
GB0222522D0 (en) | 2002-09-27 | 2002-11-06 | Controlled Therapeutics Sct | Water-swellable polymers |
US20050181030A1 (en) * | 2003-01-03 | 2005-08-18 | Mo Y. J. | Topical stabilized prostaglandin E compound dosage forms |
BRPI0408454A (pt) | 2003-03-21 | 2006-04-04 | Nexmed Holdings Inc | composiĆ§Ć£o tĆ³pica, mĆ©todo de tratar a ejaculaĆ§Ć£o precoce, e, uso da composiĆ§Ć£o |
US20050113274A1 (en) * | 2003-11-22 | 2005-05-26 | Nadir Buyuktimkin | Hydrocarbyl aminohydrocarbonoates and aminohydrocarbonol hydrocarbonoates as antimicrobial and antiviral agents |
GB0417401D0 (en) | 2004-08-05 | 2004-09-08 | Controlled Therapeutics Sct | Stabilised prostaglandin composition |
US20060286172A1 (en) * | 2005-06-03 | 2006-12-21 | Anu Mahashabde | Pharmaceutical compositions comprising prostanoid-receptor agonists and methods of making and using the same |
ITMI20051417A1 (it) * | 2005-07-22 | 2007-01-23 | Mipharm S P A | Formulazione topica in forma di gel contenente come ingredienti attivi ciclovit e lidocaina |
EP1971312A1 (fr) * | 2005-12-06 | 2008-09-24 | MonoSol Rx LLC | Compositions de films topiques pour la liberation d actifs |
GB0613333D0 (en) | 2006-07-05 | 2006-08-16 | Controlled Therapeutics Sct | Hydrophilic polyurethane compositions |
GB0613638D0 (en) | 2006-07-08 | 2006-08-16 | Controlled Therapeutics Sct | Polyurethane elastomers |
US7560489B2 (en) * | 2006-10-11 | 2009-07-14 | Nexmed Holdings, Inc. | Stabilized prostaglandin E composition |
GB0620685D0 (en) * | 2006-10-18 | 2006-11-29 | Controlled Therapeutics Sct | Bioresorbable polymers |
ES2921527T3 (es) | 2009-06-03 | 2022-08-29 | Forsight Vision5 Inc | AdministraciĆ³n de fĆ”rmaco en segmento anterior |
US8940794B2 (en) | 2011-04-07 | 2015-01-27 | Nexmed Holdings, Inc. | Methods and compositions for treating Raynaud's disease |
JP5989780B2 (ja) | 2011-09-14 | 2016-09-07 | ćć©ć¼ćµć¤ćć»ććøć§ć³ļ¼ć»ć¤ć³ć³ć¼ćć¬ć¤ćććļ¼¦ļ½ļ½ļ½ļ½ļ½ļ½ļ½ ļ¼¶ļ½ļ½ļ½ļ½ļ½ļ¼ļ¼ļ¼©ļ½ļ½ļ¼ | ē¼ęæå „č£ ē½®ććć³ę¹ę³ |
PT2911623T (pt) | 2012-10-26 | 2019-11-21 | Forsight Vision5 Inc | Sistema oftĆ”lmico para libertaĆ§Ć£o prolongada de fĆ”rmaco no olho |
US8900625B2 (en) | 2012-12-15 | 2014-12-02 | Nexmed Holdings, Inc. | Antimicrobial compounds and methods of use |
EP3283004A4 (fr) | 2015-04-13 | 2018-12-05 | Forsight Vision5, Inc. | Composition d'insert oculaire d'agent pharmaceutiquement actif cristallin ou semi-cristallin |
WO2019142015A1 (fr) * | 2018-01-18 | 2019-07-25 | Caicedo Pinto, David Felipe | Composition pharmaceutique d'administration transdermique par voie urƩtrale en gouttes pour le traitement de la dysfonction Ʃrectile |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3883576A (en) * | 1971-02-02 | 1975-05-13 | Upjohn Co | Prostaglandin E{HD 3 {B analogs |
US3826823A (en) * | 1972-09-25 | 1974-07-30 | Syntex Inc | Stabilized prostaglandin preparations |
US3875300A (en) * | 1972-12-18 | 1975-04-01 | Ortho Pharma Corp | Composition for sustained release of a medicament and method of using same |
US4136162A (en) * | 1974-07-05 | 1979-01-23 | Schering Aktiengesellschaft | Medicament carriers in the form of film having active substance incorporated therein |
US5017382A (en) * | 1979-03-21 | 1991-05-21 | National Research Development Corporation | Controlled release compositions (II) |
JPS5770816A (en) * | 1980-10-17 | 1982-05-01 | Ono Pharmaceut Co Ltd | Multilayered film preparation of prostagladin of prolonged action |
JPS58134019A (ja) * | 1982-02-05 | 1983-08-10 | Ono Pharmaceut Co Ltd | ććć¹ćæć°ć©ć³ćøć³å«ęęē¶ę¾åŗåäø層ē¶ćć¤ć«ć č£½å¤åć³ćć®č£½é ę¹ę³ |
JPS5948409A (ja) * | 1982-09-10 | 1984-03-19 | Teikoku Seiyaku Kk | ēÆę£ēęÆēē§»åäæé²å¤ |
JPS6185315A (ja) * | 1984-10-04 | 1986-04-30 | Teikoku Seiyaku Kk | ć·āćē¶č£½å¤ |
IE59361B1 (en) * | 1986-01-24 | 1994-02-09 | Akzo Nv | Pharmaceutical preparation for obtaining a highly viscous hydrogel or suspension |
US5219885A (en) * | 1987-02-16 | 1993-06-15 | Froelich Juergen | Prostaglandin E1 derivatives as pharmaceutically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration |
BR9203277A (pt) * | 1992-08-21 | 1994-03-01 | Cesar Roberto Dias Nahoum | Utilizaccao de drogas eretogenicas e respectivas metodologias de aplicacao |
US5380760A (en) * | 1993-11-19 | 1995-01-10 | Minnesota Mining And Manufacturing Company | Transdermal prostaglandin composition |
SE9501670L (sv) * | 1995-05-05 | 1996-06-10 | Perstorp Ab | OmlƤggningsset |
US20020004529A1 (en) * | 1997-10-20 | 2002-01-10 | Gary W. Neal | Methods, compositions, and kits for enhancing female sexual desire and responsiveness |
US6593369B2 (en) * | 1997-10-20 | 2003-07-15 | Vivus, Inc. | Methods, compositions, and kits for enhancing female sexual desire and responsiveness |
US6414028B1 (en) * | 1997-11-05 | 2002-07-02 | Nexmed Holdings, Inc. | Topical compositions containing prostaglandin E1 |
US6046244A (en) * | 1997-11-05 | 2000-04-04 | Nexmed Holdings, Inc. | Topical compositions for prostaglandin E1 delivery |
US5942545A (en) * | 1998-06-15 | 1999-08-24 | Macrochem Corporation | Composition and method for treating penile erectile dysfunction |
NZ509031A (en) * | 1998-06-25 | 2002-10-25 | Lavipharm Lab Inc | A disk formed from a filmogenic polymer carrying a therapeutic agent selected from a stabiliser, a solubiliser, an enhancer and a plasticiser |
US6323241B1 (en) * | 2000-01-10 | 2001-11-27 | Nexmed (Holdings) Inc. | Prostaglandin compositions and methods of treatment for male erectile dysfunction |
KR100402334B1 (ko) * | 2000-06-23 | 2003-10-22 | ķģøģ ģ½ ģ£¼ģķģ¬ | ģķė”ģ¤ķė ģøģ©ģ |
-
2003
- 2003-01-03 US US10/336,481 patent/US6841574B2/en not_active Expired - Lifetime
- 2003-12-31 DK DK03800371.1T patent/DK1585483T3/da active
- 2003-12-31 KR KR1020057012502A patent/KR20050098853A/ko not_active Application Discontinuation
- 2003-12-31 AT AT03800371T patent/ATE468098T1/de active
- 2003-12-31 AU AU2003300113A patent/AU2003300113B2/en not_active Expired
- 2003-12-31 PT PT03800371T patent/PT1585483E/pt unknown
- 2003-12-31 CN CN200380110112A patent/CN100574763C/zh not_active Expired - Fee Related
- 2003-12-31 KR KR1020117008180A patent/KR101174788B1/ko not_active IP Right Cessation
- 2003-12-31 BR BR0317924-9A patent/BR0317924A/pt not_active Application Discontinuation
- 2003-12-31 WO PCT/US2003/041658 patent/WO2004062632A1/fr active Application Filing
- 2003-12-31 DE DE60332656T patent/DE60332656D1/de not_active Expired - Lifetime
- 2003-12-31 JP JP2004566647A patent/JP2006514068A/ja active Pending
- 2003-12-31 CA CA2512015A patent/CA2512015C/fr not_active Expired - Lifetime
- 2003-12-31 ES ES03800371T patent/ES2343246T3/es not_active Expired - Lifetime
- 2003-12-31 EP EP03800371A patent/EP1585483B1/fr not_active Expired - Lifetime
-
2005
- 2005-06-27 IL IL169425A patent/IL169425A/en unknown
- 2005-06-30 ZA ZA200505321A patent/ZA200505321B/en unknown
-
2006
- 2006-10-05 HK HK06111022.3A patent/HK1090293A1/xx not_active IP Right Cessation
-
2011
- 2011-09-14 JP JP2011200752A patent/JP5395138B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
IL169425A (en) | 2010-11-30 |
CA2512015A1 (fr) | 2004-07-29 |
DK1585483T3 (da) | 2010-07-19 |
AU2003300113A1 (en) | 2004-08-10 |
ZA200505321B (en) | 2006-04-26 |
US20040131664A1 (en) | 2004-07-08 |
JP2006514068A (ja) | 2006-04-27 |
ES2343246T3 (es) | 2010-07-27 |
KR101174788B1 (ko) | 2012-08-20 |
JP5395138B2 (ja) | 2014-01-22 |
EP1585483A1 (fr) | 2005-10-19 |
HK1090293A1 (en) | 2006-12-22 |
KR20050098853A (ko) | 2005-10-12 |
KR20110042138A (ko) | 2011-04-22 |
AU2003300113B2 (en) | 2010-03-11 |
PT1585483E (pt) | 2010-06-17 |
US6841574B2 (en) | 2005-01-11 |
BR0317924A (pt) | 2005-11-29 |
JP2012036196A (ja) | 2012-02-23 |
WO2004062632A1 (fr) | 2004-07-29 |
CN100574763C (zh) | 2009-12-30 |
ATE468098T1 (de) | 2010-06-15 |
EP1585483A4 (fr) | 2006-04-19 |
CA2512015C (fr) | 2011-11-08 |
DE60332656D1 (de) | 2010-07-01 |
CN1756532A (zh) | 2006-04-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5395138B2 (ja) | å±ęå®å®åććć¹ćæć°ć©ć³ćøć³ļ½ ååē©å¤å½¢ | |
CA2592978C (fr) | Forme dosifiee d'un compose de prostaglandine de groupe e stabilise topique | |
EP1028708B1 (fr) | Compositions topiques pour l'administration de prostaglandine e1 | |
US7560489B2 (en) | Stabilized prostaglandin E composition | |
AU2014201174B2 (en) | Stabilized prostaglandin e composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20050714 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20060302 |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20061218 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
GRAC | Information related to communication of intention to grant a patent modified |
Free format text: ORIGINAL CODE: EPIDOSCIGR1 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61K 9/14 20060101ALI20091130BHEP Ipc: A61K 9/00 20060101ALI20091130BHEP Ipc: A61K 31/19 20060101ALI20091130BHEP Ipc: A61K 31/557 20060101ALI20091130BHEP Ipc: A61F 13/00 20060101ALI20091130BHEP Ipc: A61L 15/16 20060101ALI20091130BHEP Ipc: A61K 9/70 20060101ALI20091130BHEP Ipc: A61K 8/00 20060101AFI20091130BHEP |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: NEXMED HOLDINGS, INC. |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: SERVOPATENT GMBH Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: SC4A Free format text: AVAILABILITY OF NATIONAL TRANSLATION Effective date: 20100609 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REF | Corresponds to: |
Ref document number: 60332656 Country of ref document: DE Date of ref document: 20100701 Kind code of ref document: P |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: TRGR |
|
REG | Reference to a national code |
Ref country code: RO Ref legal event code: EPE |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: EP Ref document number: 20100401469 Country of ref document: GR |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2343246 Country of ref document: ES Kind code of ref document: T3 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: T3 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20100519 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20100519 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20100519 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20100519 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20100519 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
REG | Reference to a national code |
Ref country code: HU Ref legal event code: AG4A Ref document number: E009232 Country of ref document: HU |
|
26N | No opposition filed |
Effective date: 20110222 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 60332656 Country of ref document: DE Effective date: 20110221 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20101231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20101231 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 13 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 14 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20151231 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: TR Payment date: 20161209 Year of fee payment: 14 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PUE Owner name: FERRING INTERNATIONAL CENTER S.A., CH Free format text: FORMER OWNER: NEXMED HOLDINGS, INC., US |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R082 Ref document number: 60332656 Country of ref document: DE Representative=s name: ZSP PATENTANWAELTE PARTG MBB, DE Ref country code: DE Ref legal event code: R081 Ref document number: 60332656 Country of ref document: DE Owner name: FERRING INTERNATIONAL CENTER S.A., CH Free format text: FORMER OWNER: NEXMED HOLDINGS, INC., SAN DIEGO, CALIF., US |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP Owner name: FERRING INTERNATIONAL CENTER S.A, CH Effective date: 20170518 |
|
REG | Reference to a national code |
Ref country code: HU Ref legal event code: FH1C Free format text: FORMER REPRESENTATIVE(S): DR. KISS ILDIKO, DANUBIA SZABADALMI ES JOGI IRODA KFT., HU Representative=s name: DANUBIA SZABADALMI ES JOGI IRODA KFT., HU Ref country code: HU Ref legal event code: GB9C Owner name: FERRING INTERNATIONAL CENTER S.A., CH Free format text: FORMER OWNER(S): NEXMED HOLDINGS, INC., US |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E Free format text: REGISTERED BETWEEN 20170803 AND 20170809 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20151231 |
|
PGRI | Patent reinstated in contracting state [announced from national office to epo] |
Ref country code: IT Effective date: 20170710 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: PD Owner name: FERRING INTERNATIONAL CENTER S.A.; CH Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), ASSIGNMENT; FORMER OWNER NAME: NEXMED HOLDINGS, INC. Effective date: 20170818 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: PC2A Owner name: FERRING INTERNATIONAL CENTER S.A. Effective date: 20171025 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 15 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: PC Ref document number: 468098 Country of ref document: AT Kind code of ref document: T Owner name: FERRING INTERNATIONAL CENTER S.A., CH Effective date: 20170918 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: RO Payment date: 20171122 Year of fee payment: 15 Ref country code: HU Payment date: 20171115 Year of fee payment: 15 Ref country code: FR Payment date: 20171113 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GR Payment date: 20171113 Year of fee payment: 15 Ref country code: BE Payment date: 20171024 Year of fee payment: 15 Ref country code: BG Payment date: 20171027 Year of fee payment: 15 Ref country code: AT Payment date: 20171128 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DK Payment date: 20180327 Year of fee payment: 15 Ref country code: CH Payment date: 20180328 Year of fee payment: 15 Ref country code: GB Payment date: 20180321 Year of fee payment: 15 Ref country code: FI Payment date: 20180326 Year of fee payment: 15 Ref country code: ES Payment date: 20180327 Year of fee payment: 15 Ref country code: DE Payment date: 20180320 Year of fee payment: 15 Ref country code: NL Payment date: 20180328 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IE Payment date: 20180326 Year of fee payment: 15 Ref country code: IT Payment date: 20180322 Year of fee payment: 15 Ref country code: SE Payment date: 20180326 Year of fee payment: 15 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: PT Payment date: 20180406 Year of fee payment: 15 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R119 Ref document number: 60332656 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EBP Effective date: 20181231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MM Effective date: 20190101 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MM01 Ref document number: 468098 Country of ref document: AT Kind code of ref document: T Effective date: 20181231 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20181231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: RO Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190101 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20181231 Ref country code: IE Ref legal event code: MM4A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190701 Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190702 Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190101 Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190630 Ref country code: GR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190702 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 Ref country code: HU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190101 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20200205 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20190101 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20181231 |